1. Carcinogenesis. 2007 Nov;28(11):2367-74. Epub 2007 May 17.
Identification and chromosome mapping of loci predisposing to colorectal cancer
that control Wnt/beta-catenin pathway and progression of early lesions in the
rat.
De Miglio MR(1), Virdis P, Calvisi DF, Mele D, Muroni MR, Frau M, Pinna F, Tomasi
ML, Simile MM, Pascale RM, Feo F.
Author information:
(1)Department of Biomedical Sciences, Division of Experimental Pathology and
Oncology, University of Sassari, 07100 Sassari, Italy.
Sporadic colorectal cancer (CRC) is a major health concern worldwide.
Epidemiologic evidence suggests a polygenic predisposition to CRC, but the genes
responsible remain unknown. Here, we performed genome-wide scanning of male
(ACI/SegHsd x Wistar-Furth)F2 (AWF2) rats to map susceptibility genes influencing
the evolution of early colorectal lesions to adenocarcinoma following
1,2-dimethylhydrazine administration. Phenotypic analysis revealed higher
incidence/multiplicity and lower size of adenomas in ACI/SegHsd (ACI) and
(ACI/SegHsd x Wistar-Furth)F1 (AWF1) than Wistar-Furth (WF) rats and higher
incidence/multiplicity of poorly differentiated adenocarcinomas in WF than ACI
rats, with intermediate values in AWF1 rats. Linkage analysis of 138 AWF2 rats
identified three loci on chromosomes 4, 15 and 18 in significant linkage with
lesion multiplicity that were identified as rat Colon cancer resistance (rCcr) 1,
rCcr2 and rCcr3, respectively. Seven other loci on chromosomes 5, 6, 15, 17, 18
and 20 were in suggestive linkage with adenoma/adenocarcinoma
multiplicity/surface area. Six of them were identified as rCcr4-9 and a locus on
chromosome 5 was identified as a susceptibility locus, rCcs1. Significant
interactions between rCcr3 and rCcr6, rCcr6 and rCcr8 and rCcr5 and rCcr9, and
four novel epistatic loci controlling multiplicity/size of colorectal lesions
were discovered. Apc, located at rCcr3, did not show functional promoter
polymorphisms. However, influence of susceptibility/resistance genes on
Wnt/beta-catenin pathway was shown by defective beta-catenin inactivation in WF
but not in ACI and AWF1 rat adenocarcinomas. These data indicate that inheritance
of predisposition to CRC depends on interplays of several genetic factors, and
suggest a possible mechanism of polygenic control of CRC progression.
PMID: 17510081 [PubMed - indexed for MEDLINE]
PUBMED: 17510081
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